Project Summary/Abstract Conventional risk factors such as hypercholesterolemia, diabetes and hypertension are incompletely predictive of cardiovascular disease (CAD), suggesting additional unidentified risk factors. Recent studies have identified clonal hematopoiesis of indeterminate potential (CH) as a new cardiovascular risk factor and a potential major driver of atherosclerosis in the elderly. CH is caused by mutations that endow a proliferative advantage to hematopoietic stem cells, commonly involving epigenetic modifiers (TET2, DNTM3a, ASXL1) or signaling pathways (JAK2). Understanding the mechanisms underlying the association of CH with CAD is highly relevant in precision medicine and has the potential to lead to novel targeted therapies for CAD. Acquired activating mutations of JAK2 in hematopoietic tissues, with JAK2V617F (JAK2VF) as the most common, drive development of myeloproliferative disorders and CH; amongst the different CH genetic variants JAK2VF is most clearly associated with increased risk of CAD. Until recently the causal relationship had not been directly assessed. We published a study recently using a mouse model carrying the authentic human like Jak2VF mutation and demonstrated potent pro- atherogenic effects of hematopoietic Jak2VF expression. In this proposal, we will follow the leads and generate novel mouse models including hematopoietic lineage specific Jak2VF expression and Jak2VF-driven CH to explore the mechanisms underlying Jak2VF-driven atherosclerosis. A deeper understanding of these mechanisms may lead to development of new therapeutic approaches to managing CH-associated CVD risks, as will be evaluated in this proposal.